Changing levels of the ovarian hormones 17?-estradiol (E2) and progesterone (PROG), together with their neuroactive metabolites, have essential actions on the central nervous system (CNS). Many of the CNS effects involve memory and mood disorders such as those found in women after menopause, or the cognitive and psychiatric symptoms frequently present during specific stages of the menstrual cycle. Yet, little is known about how large swings in ovarian hormone levels affect the coordination of neuronal ensembles in the brain during behavior and how particular abnormalities may ensue at the cellular or molecular level. This proposal focuses on the function of parvalbumin-positive (PV+) interneurons (INs) as collective mediators of cognitive and emotional states associated with altered ovarian hormone levels. These cells and the networks they control are critically involved in sharp-wave ripples (SPW-R) and ?-oscillations (30-120 Hz), brain rhythms essential for memory recall, cognition, and information processing. We hypothesize that E2 and PROG act on PV+INs through distinct mechanisms to alter SPW-R, ?-oscillatory activity, and/or phase-amplitude coupling between ? (5-10 Hz) and ?-oscillations. Two novel mechanisms will be investigated: the function of ? subunit- containing ?-amino-butyric-acid receptors (?-GABAARs) of PV+INs as a target for PROG-derived neurosteroids (NS); and the signaling cascade formed by the G-protein coupled E2 receptor (GPER-1) ? neuregulin 1 (NRG-1) ? endothelial growth factor receptor tyrosine kinase (ErbB4), for E2. Two periods of ovarian hormonal alterations will be examined in mice. The first is the physiological ovarian cycle in which E2 and PROG levels rapidly swing up and down over a typical cycle period of 4-6 days. The second is a genuine model of human menopause in mice, that is, the selective attrition of small primordial and primary ovarian follicles by the industrial chemical 4-vinylcyclohexene diepoxide (VCD) that has negligible effects on other tissues. These studies will provide the experimental underpinnings of the first comprehensive and unifying model of ovarian hormone action on neuronal oscillations underlying cognition and working memory. Sophisticated electrophysiological and optogenetic experiments in vivo and in vitro, genetic manipulations, pharmacological approaches never before tested for effects on neuronal ensembles, and morphological/immunohistochemical studies carried out for the first time in this context will converge in the proposal. This multifaceted and novel approach is expected to provide unique insights into the actions of ovarian hormonal changes on the female brain. The studies have a high translational potential as they will shed light on possible treatments for millions suffering from menstrual cycle-related neurological and psychiatric dysfunction (pre-menstrual syndrome, PMS, and pre-menstrual dysphoric disorder, PMDD), and may provide explanation for the cognitive decline and high prevalence of sporadic Alzheimer's disease (AD) in post-menopausal women.